Process for the preparation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide

ABSTRACT

A process for producing an acridine carboxamide of formula (I): ##STR1## wherein each of R 1 , R 2 , R 5  and R 6 , which may be the same or different, is H or an organic subsituent, x is from 1 to 6 and Y is N(R)2 wherein R is C 1  -C 6  alkyl, or a pharmaceutically acceptable salt thereof.

This is a 35 U.S.C. § 371 of PCT/GB97/02884 filed Oct. 17, 1997.

The present invention relates to a new process for the production of theanti-cancer drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide andderivatives thereof.

The acridine derivativeN-[(2-dimethylamino)ethyl]acridine-4-carboxamide, known as DACA, is anew DNA-intercalating agent with inhibitory activity against the enzymestopoisomerase I and topoisomerase II (Schneider et al, Eur. J. CancerClin. Oncol, 1988, 24 1783 and Finlay, et al Eur J. Cancer 1996, 32A708). It has a wide spectrum of activity against solid tumours inanimals and is relatively unaffected by P-glycoprotein-mediatedmultidrug resistance (Atwell et al, J. Med Chem, 1987, 30, 664, Baguleyet al, Cancer Chemother. Pharmacol 1995, 36, 244 and Finlay et al CancerChemother. Pharmacol. 1993, 31,401). Certain analogues of DACA have beenreported, and many have shown significant activity in a mouse solidtumour (Atwell et al, ibid).

The known process for producing DACA, reported by twell et al, ibid, isshown in Scheme 1. ##STR2##

Step (i) comprises reduction of the acridone (1) by treatment withaluminium/mercury amalgam in the presence of KOH in aqueous ethanolunder reflux, followed by reoxidation of the resulting acridan withFeCl₃, to give the intermediate acridine carboxylic acid (2). Step (ii)comprises treatment of the acid (2) with 1,1-carbonyldiimidazole (CDI)and dimethylformamide, followed by N,N-dimethylethylenediamine.

Various disadvantages are associated with this process. One is that thereductive conditions required in step (i) are harsh. This limits thescope of the process and makes it unsuitable for the production ofcertain analogues of DACA which bear reduction-sensitive substituents onthe acridine nucleus. For instance, dechlorination has been observedwhen the process has been applied to the production ofchloro-substituted derivatives of DACA. Another disadvantage of theknown process is that the intermediate acridine carboxylic acids (2)have severe lachrymatory and sternutatory properties, which limit theiruse.

It has now been found that DACA and derivatives thereof can be producedby a process which comprises cyclising an aldehyde precursor whichincludes an esterified, rather than a free, carboxylic acid functionalgroup and then subjecting that esterified group in the cyclised productdirectly to treatment with a primary alkyl amine. If desired theesterified group in the cyclised product can first be hydrolysed togenerate a free carboxylic acid function, which is then treated with theprimary alkyl amine in the presence of a suitable coupling agent. Thealdehyde precursor is readily produced by oxidation of the correspondingalcohol, which in turn is produced by mild reduction of thecorresponding carboxylic acid via an imidazolide intermediate.

Accordingly, the present invention provides a process for producing anacridine carboxamide of formula (I): ##STR3## wherein each of R¹, R², R⁵and R⁶, which may be the same or different, is H, C₁ -C₆ alkyl, C₁ -C₆alkoxy, aryloxy, aralkyloxy, halogen, phenyl, CF₃, NO₂, NH₂, N(R)₂,NHCOR, NHCOOR, NHR⁴, OH, SH, SR or S (R)₂, wherein R⁴ is H, COR, SO₂ R,COPh, SO₂ Ph or C₁ -C₆ alkyl unsubstituted or substituted by OH oramino, and R is C₁ -C₆ alkyl; or R¹ and R₂, or R₅ and R₆, together forma methylenedioxy group; x is an integer of 1 to 6 and Y is N(R)₂ asdefined above; or a pharmaceutically acceptable salt thereof; whichprocess comprises:

(a) cyclising a compound of formula (II) ##STR4## wherein R¹, R², R⁵ andR⁶ are as defined above and R³ is C₁ -C₆ alkyl, aryl or aryl-C₁ -C₃-alkyl, by treatment with a Lewis acid in an organic solvent, to obtaina compound of formula (III): ##STR5## wherein R¹, R², R³, R⁵ and R⁶ areas defined above; and

(b) treating either (i) the compound of formula (III) as defined abovewith a primary alkylamine of formula (IV)

    NH.sub.2 (CH.sub.2).sub.x Y                                (IV)

wherein X and Y are as defined above, or (ii) the carboxylic acidobtainable by hydrolysing the compound of formula (III) as definedabove, under basic conditions, with a primary alkyl amine of formula(IV) as defined above in the presence of a suitable coupling agent, toobtain a compound of formula (I) as defined above; and

(c) if desired, converting one compound of formula (I) into anothercompound of formula (I), and/or converting a compound of formula (I)into a pharmaceutically acceptable salt thereof.

In a preferred embodiment of this process R¹, R², R⁵ and R⁶ in formula(II) are H, and in formula (IV) x is 2 and Y is NMe₂. The resultingcompound of formula (I) is thenN-[(2-dimethylamino)ethyl]acridine-4-carboxamide (DACA).

Any suitable Lewis acid may be employed in step (a). An example istrifluoroacetic acid, which is used under nitrogen at room temperature.Alternatively step (a) may be performed by treatment of the compound offormula (II) with either borontrifluoride or a suitable complex thereofin a suitable solvent. Suitable complexes include the acetic acidcomplex. In one embodiment, a slight excess of 1 1/3 moles of BF₃ (thestoichiometric amount) would be used, for instance 2 molar equivalents.The BF₃ is typically used in the form of its etherate BF₃ O(Et)₂.Suitable solvents for use with BF₃ O(Et)₂ include EtOAc and CH₂ Cl₂. Thecompound of formula (III) is then obtained in either case in the form ofits tetrafluoroborate salt of formula (IIIa): ##STR6## wherein R¹, R²R³, R⁵ and R⁶ are as defined above.

When BF₃ is used, generation of the tetrafluoroborate salt (IIIa) can berepresented as follows: ##STR7##

The tetrafluoroborate salt of formula (IIIa) precipitates out from thereaction mixture and can be removed easily by filtration. Addition of aninorganic base, for instance sodium carbonate, and a solvent such asethyl acetate or dichloromethane to the filtered solid generates thecompound of formula (III). This can then be treated further with anamine of formula (IV). Advantages of this procedure are that thetetrafluoroborate salt is produced in almost quantitative yield, and canreadily be subjected to further reaction without the need to separateexcess reagents or side products. This facilitates operation of theprocess of the invention on an industrial scale, particularly sincethrough-put can be increased.

It may in some cases be desirable to hydrolyse the compound of formula(III) to the corresponding acid prior to treatment with the amine offormula (IV) in step (b). This may be, for example, if the compound offormula (III) itself is unstable to oxidation. The hydrolysis is carriedout under mild basic conditions, for instance by treatment with analkali metal hydroxide (e.g. NaOH or KOH) in a solvent such as ethanol.Any suitable coupling agent may be used in the reaction of the acid withthe amine of formula (IV) in step (b), for example1,1'-carbonyldiimidazole.

The compound of formula (II) is produced by oxidising the correspondingalcohol of formula (V): ##STR8## wherein R¹, R², R³, R⁵ and R⁶ are asdefined above.

The oxidation is performed under any suitable oxidising conditions.Manganese (IV) oxide (MnO₂), for instance in solid form in a polarsolvent such as ethyl acetate or acetone, is a preferred oxidisingagent. MnO₂ may, for instance, be added as a suspension in acetone tothe alcohol of formula (V) and allowed to react at room temperature. Thereaction then typically takes several days, for instance 2 or 3 days, toreach completion. Alternatively, a mixture of the alcohol of formula (V)and MnO₂ in ethyl acetate may be ref luxed together, for exampleovernight.

The alcohol of formula (V) is produced by

(a) treating a compound of formula (VI): ##STR9## wherein R¹, R², R³, R⁵and R⁶ are as defined above, with 1,1'-carbonyldiimidazole in a polarsolvent, to obtain a compound of formula (VII): ##STR10## wherein R¹,R², R³, R⁵ and R⁶ are as defined above, and

(b) reducing the imidazolide of formula (VII) as defined above.

In step (a) above the polar organic solvent may be, for instance, THF.The reactants are typically stirred at room temperature until thereaction is complete. In step (b) the reduction is typically performedby treatment of the compound of formula (VII) with an excess of ametal-based reducing agent, for instance sodium borohydride. In thiscase the solution which results from step (a) may suitably be added to astirred suspension of sodium borohydride in water.

The use of the intermediate imidazolide of formula (VII) allows thereduction of carboxylic acids of formula (VI) to alcohols of formula (V)to take place relatively easily under mild conditions.

The compounds of formula (VI) are known compounds or may be produced byknown methods, for instance by heating together an anthranilic acid offormula (VIII): ##STR11## wherein R¹ and R² are as defined above, and a2-iodobenzoic acid ester of formula (IX): ##STR12## wherein R³, R⁵ andR⁶ are as defined above, in the presence of a copper catalyst and a basein a polar solvent.

The copper catalyst suitably comprises a copper (I) halide and copperpowder. The polar solvent may be, for instance, ethylene glycol orbutane-2,3-diol. Any suitable base may be used, for instance N-ethylmorpholine.

In the compounds of formula (I) produced by the process of theinvention, the substituents R¹ and R² may occupy any one of ringpositions 5 to 8, and substituents R⁵ and R⁶ may occupy any one of ringpositions 1 to 4, in the tricyclic chromophore. Thus R¹ and R² may eachbe bonded to any one of the ring positions in the starting compounds andintermediates of formulae (III) and (V) to (VIII) which correspond topositions 5 to 8 of the final compounds of formula (I). Similarly, R⁵and R⁶ may be bonded to any one of the ring positions in the startingmaterials and intermediates of formulae (III) and (V) to (VIII) whichcorrespond to positions 1 to 4 of the final compounds of formula (I).

In one preferred series of compounds R⁵ and R⁶ are both H. In thisseries the compounds are of the general formula (Ia): ##STR13## whereinR¹, R², x and y are as defined above for formula (I). Formula (Ia) isthus a preferred embodiment of formula (I). Typically one of R¹ and R²is hydrogen and the other is hydrogen or a substituent as defined abovefor formula (I) bonded at any one of ring positions 5 to 8.

In a preferred series of compounds of formula (I) each of R¹ and R²,which may be the same or different, is H, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,halogen, phenyl, CF₃, NO₂, NH₂, N(R)₂ as defined above or OH, x is aninteger of 1 to 3 and Y is N(R)₂ as defined above.

Typically R¹ is H and R² is H or a substituent other than H bonded atposition 5, 6 or 7 of the acridine nucleus in formula (I). For instance,R¹ is H and R₂ is at position 5 and is C₁ -C₆ alkyl, CF₃, phenyl,halogen or a group N(R)₂ ; or R¹ is H and R² is at position 6 and ishalogen, CF₃ or N(R)₂ as defined above; or R¹ is H and R² is at position7 and is C₁ -C₆ alkyl, phenyl, OH, halogen, CF₃ or N(R)₂.

Alternatively R¹ is other than hydrogen. For instance, when R² is atposition 5 as defined above, R¹ is at position 6, 7 or 8, preferably 6or 7, and is C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halogen, phenyl, CF₃, NO₂,NH₂, N(R)₂ as defined above, or OH. When R² is at position 6 as definedabove R¹ is at position 5, 7 or 8, preferably 5 or 7, and is C₁ -C₆alkyl, C₁ -C₆ alkoxy, halogen, phenyl, CF₃, NO₂, NH₂, N(R)₂ or OH. WhenR² is at position 7 as defined above, R¹ is at position 5, 6 or 8,preferably 5 or 6, and is C₁ -C₆ alkyl, C₁ -C₆ alkoxy, halogen, phenyl,CF₃, NO₂, NH₂ N(R)₂ or OH.

A C₁ -C₆ alkyl group may be linear or branched, and is, for example C₁-C₄ alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl ort-butyl. A C₁ -C₆ alkoxy group may also be linear or branched, and is,for example, C₁ -C₄ alkoxy such as methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy or t-butoxy. A halogen is, for example,fluorine, chlorine, bromine or iodine. An aryl group is, for example, aC₆ -C₁₂ aryl group such as phenyl or naphthyl. The aryl moiety in anaryl-C₁ -C₃ -alkyl, aralkyloxy or aryloxy group may be a C₆ -C₁₂ arylgroup, for instance phenyl or naphthyl. Examples of a aryl-C₁ -C₃ -alkylgroup thus include phenyl-C₁ -C₃ -alkyl groups, such as benzyl andphenylethyl.

The compounds of formula (I) may be converted into pharmaceuticallyacceptable acid addition salts, by conventional methods. For instance,the acid addition salts may be prepared by contacting the free base withan appropriate amount of the desired acid in a conventional manner.Suitable salts include salts with both organic and inorganic acids.Examples of suitable acids are hydrochloric, sulfuric, phosphoric,acetic, citric, oxalic, malonic, salicylic, maleic, fumaric, succinic,ascorbic, methanesulfonic and the like. Depending on structure, and onthe conditions, the compounds may form multicationic forms.

The optional conversion of a compound of formula (I) into anothercompound of formula (I) may be carried out by conventional methods. Forinstance, a fluoro group in a compound of formula (I) may be replaced byan amino or thiol group to give an amine or thioether, respectively; athiol group in a compound of formula (I) may be alkylated to give athioether; an amino group may be acylated to give an N-acetyl group; anda nitro group may be reduced to give an amine. These are all routineconversions in organic chemistry.

The amines of general formula (IV) are known compounds, and arecommercially available or preparable by methods described in theliterature. Specific examples of such compounds include NH₂ (CH₂)₂ NMe₂[x is 2 and Y is N(CH₃)₂ ].

The compounds of formula (I) and their salts produced by the process ofthe invention may be formulated for use as a pharmaceutical orveterinary composition. The process of the present invention as definedabove may therefore further comprise formulating a compound of formula(I) or a pharmaceutically acceptable salt thereof with apharmaceutically or veterinarily acceptable carrier or diluent to form apharmaceutical or veterinary composition. The composition is typicallyprepared following conventional methods such that it is suitable foradministration to a human or animal patient.

The composition may be formulated in a variety of dosage forms, forexample for oral administration such as in the form of tablets,capsules, sugar- or film-coated tablets, liquid solutions orsuspensions, or for parenteral administration, for exampleintramuscularly, intravenously or subcutaneously. The compounds offormula (I) may therefore be formulated for injection or infusion.

For example, the solid oral forms may contain, together with the activecompound, diluents, such as lactose, dextrose, saccharose, cellulose,corn starch or potato starch; lubricants such as silica, talc, stearicacid, magnesium or calcium stearate and/or polyethylene glycols; bindingagents such as starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agentssuch as starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures, dye-stuffs; sweeteners; wetting agents such aslecithin, polysorbates, laurylsulphates. Such preparations may bemanufactured in known manner, for example by means of mixing,granulating, tabletting, sugar coating, or film-coating processes.

Liquid dispersions for oral administration may be syrups, emulsions andsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular a syrup may contain as carrier, for example, saccharose orsaccharose with glycerol and/or mannitol and/or sorbitol. In particulara syrup for diabetic patients can contain as carriers only products, forexample sorbitol, which do not metabolise to glucose or which onlymetabolise a very small amount to glucose. The suspensions and theemulsions may contain as carrier, for example a natural gum, agar,sodium alginate, pectin, methylcellulose, carboxymethylcellulose orpolyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptable carriersuch as sterile water, olive oil, ethyl oleate, glycols such aspropylene glycol, ad if desired, a suitable amount of lidocainehydrochloride. Typically the compounds of formula (I) are formulated asaqueous solutions of hydrochloride or other pharmaceutically acceptablesalts. Solutions for intravenous injection or infusion may contain acarrier, for example, sterile water which is generally Water forInjection.

The invention will be further described in the Examples which follow:

EXAMPLE 1 Preparation of Methyl 2-[N-(2-carboxyuhenyl)amino]benzoate.##STR14##

A mixture of anthranilic acid (16.48 g, 120 mmol), methyl 2-iodobenzoate(39.3 g, 150 mmol), N-ethyl morpholine (38.1 ml; 34.5 g, 300 mmol),ethylene glycol (120 ml), cuprous chloride (3 g) and copper powder (99%;0.6 g) was stirred in an oil bath at 140° C. for 6 hours (internaltemperature, ca 130° C.). The reaction mixture was cooled and slowlypoured into a stirred mixture of ethyl acetate (300 ml) and 1Mhydrochloric acid (300 ml) after which the mixture was filtered toremove insoluble interfacial material. The bed was washed with ethylacetate (200 ml).

After separation of the organic phase from the filtrate, the aqueouslayer was then extracted in succession with the ethyl acetate washes(2×100 ml) of the above filter bed. The combined organic extracts werestirred with activated carbon (3 g) and filtered. The filtrate wasextracted with ca 1.5% aqueous ammonia solution (1×400 ml and 2×150 ml).The combined ammoniacal extracts were added slowly to a stirred excessof 1M hydrochloric acid and the product was collected by filtration,washed with hot water (3×100 ml) and pulled dry (wet weight, ca 60 g).After drying in vacuo at 55° C., the title compound was obtained (27.8g. 85.4%). (Purity by hplc ˜90% a/a; major impurity was thecorresponding dicarboxylic acid). mp196-198° C. ¹ HNMR(CDCl₃)δ3.93 (3,sCOOMe), 6.92 (2H, m, J=7.5, H-4, H-4'), 7.26 (s, solvent CHCl₃), 7.38(2H, m,H-5, H-5'), 7.51 (2H, br.t, J=8.9, H-6, H-6'), 7.98 (1H,dd, J=7.9and 1.1, H-3'), 8.09 (1H, J=7.9, H-3), 10.82 (1H,br.s,NH).

EXAMPLE 2 Preparation of Methyl 2-[N-(2-hydroxymethyl)phenylamino]benzoate. ##STR15##

1,1'-Carbonyl diimidazole (19.5 g, 120 mmol) was added to the productproduced in Example 1, (27.1 g, 100 mmol) in THF (hplc grade, 270 ml)and the mixture was stirred overnight at room temperature to give alight brown solution of the imidazolide intermediate. Tlc (SiO₂ : 10%MeOH/CH₂ Cl₂ with visualisation under UV at 254 nm) indicated thereaction was complete.

This solution was added over 30 minutes to a stirred suspension ofsodium borohydride (12.5 g, 330 mmol) in water (375 ml). Initially, ayellow gum deposited which, by the end of the addition, had changed to agreyish yellow suspension and the temperature was 37° C. Tlc (SiO₂:EtOAc with visualisation under UV at 254 nm) indicated the reductionwas complete. After stirring the suspension for a further 30 min, theexcess sodium borohydride was destroyed by the addition of conc. HCl (35ml) keeping the temperature below 30° C. by means of an ice bath. The pHof the mixture was ca 7. EtOAc (300 ml) and saturated sodium hydrogencarbonate solution (200 ml) was added and the mixture was stirred for ashort time after which the organic phase was separated. (volume ofdiscarded aqueous phase, 690 ml). The pale yellow organic solution waswashed with brine (100 ml) separated and concentrated in vacuo.Re-evaporation from EtOAc (3×100 ml) gave the title compound (27.6g>100%) as a yellowish brown oil, Hplc ca 90% a/a. A sample slowlycrystallised on storage, mp 69-71° C. ¹ H NMR (CDCl₃)δ1.93 (br.s,1H,OH), 3.91 (s,3H, COOCH₃), 4.72 (s,2H, CH₂ OH), 6.74 (ddd, J=8.0, 7.0,1.1 Hz, 1H, H-5), 7.08-7.44 (m,6H,H-3,3',4,4',5',6'), 7.97 (dd, J=8.0,1.6 Hz,1H, H-6), 9.59 (br.s, 1H, NH).

EXAMPLE 3 Preparation of Methyl 2-[N-(2-formyl)phenyl amino]benzoate##STR16##

The product of Example 2 (27.6 g ca 100 mmol) in EtOAc (300 ml) wasstirred with manganese (IV) oxide (<5 micron, activated ˜85% MnO₂). (55g, 2 wts) and refluxed overnight (17 h). Tlc (SiO₂ :EtOAc) visualisedunder UV at 254 nm (in daylight the aldehyde can be seen as a yellowspot) indicated complete reaction. Activated charcoal (2.7 g) andKieselguhr (2.7 g) were added to the warm mixture which was stirred for30 minutes and filtered through a Kieselguhr bed. The bed was washedwith EtOAc (2×100 ml).

The bright yellow filtrate was carefully concentrated in vacuo to halfvolume, removed from the evaporator and washed with water (50 ml). Theorganic phase was separated, concentrated in vacuo to a low volume(wt,47 g) when crystallisation of the product started and the residueset to an intense yellow solid. Hexane (200 ml) was added with stirringto break up the crystalline mass and after 1 hour the product wasfiltered, washed with hexane and dried in vacuo at 40° C. to give thetitle compound (19.6 g, 76.7%) HPLC 94.5% a/a. mp 110-112° C. ¹ HNMR(CDCl₃)δ3.95 (s, 3H, COOCH₃), 6.95-7.03 (m, 2H, H-4',5), 7.41-7.45(m,2H,H-5'6), 7.50 (br d, J=8.5 Hz, 1H, H-3 or H-6'), 7.61 (br d, J=8.2Hz, 1H, H-6' or H-3), 7.65 (dd, J=7.7, 1.7 Hz, 1H, H-3'), 8.01 (dd,J=7.9, 1.7 Hz, 1H, H-6), 10.00 (s, 1H, CHO) 11.26 (br s, 1H, NH)

EXAMPLE 4 Preparation of Methyl acridine-4-carboxylate. ##STR17##

The aldehyde produced in Example 3 (12.75 g, 50 mmol) in degassed ethylacetate (250 ml) was stirred under nitrogen and borontrifluoride aceticacid complex (25 ml, 33.8 g, 180 mmol) was added over 15 minutes. Beforethe addition was complete, the tetrafluoroborate salt began tocrystallise as an orange solid. The mixture was left to stir undernitrogen at room temperature overnight. The thick orange precipitate wasremoved by filtration, washed with EtOAc (20 ml), hexane (50 ml) andpulled dry on the filter. (20 g. ca 92% pure by Hplc).

This solid was added to a mixture of EtOAc (250 ml) and saturated sodiumcarbonate solution (150 ml). The pale yellow organic layer was separatedand washed with saturated brine solution (30 ml). Tlc (SiO₂ : 10% MeOHin CH₂ Cl₂ visualised under UV at 254 nm) showed essentially one spot.The organic solution was evaporated in vacuo to give the title compound(11.5 g, 97%) as a pale yellow oil which readily crystallised. HPLCindicated this was ca 90% pure. The material was used without furtherpurification for the preparation of DACA. ¹ H NMR (CDCl₃)δ4.12 (s,3H,COOCH₃), 7.53-7.58 (m,2H, H-2 and H-6 or H-7), 7.79 (ddd, J=8.8, 6.6,1.4 Hz, 1H, H-7 or H-6), 8.00 (dd, J=8.0, 1.0 Hz, 1H, H-1) 8.12-8.14(m,2H, H-5,8), 8.30 (dd, J=8.7, 0.9 Hz, 1H, H-3), 8.80 (s, 1H, H-9).

EXAMPLE 5 Preparation ofN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). ##STR18##

Methyl acridine-4-carboxylate produced as in Example 4, (11.2 g, 47mmol) was diluted with N,N-dimethyl ethylenediamine (20 ml, 16.2 g, 184mmol) and the solution was distilled down on a rotary evaporator toremove traces of residual EtOAc (loss in wt. ca 1.5 g). The mixture wasthen heated under nitrogen in an oil bath at 120° C. for 7 hours andleft to cool over night in the bath. The mixture was dissolved intoluene (50 ml) and concentrated to a gum in vacuo.

The residue was dissolved in EtOAc (150 ml) and washed with 1M aqueoussodium carbonate solution (2×100 ml). The organic layer was separated,stirred with activated charcoal (1.5 g) and Kieselguhr (1.5 g), andfiltered through a Keiselguhr bed. The bed was washed with EtOAc and thefiltrate and washes were concentrated in vacuo to a yellowish brown oilwhich rapidly crystallised to a buff solid which was triturated withhexane (100 ml) and filtered to give title compound as a pale buffsolid, washed with hexane (50 ml) and dried in vacuo at 40° C. (10.4 g,75.4%)HPLC, 90-95% a/a, mp 105-108° C. ¹ HNMR (DMSO)δ2.34 (6H,s,N(CH₃)₂), 2.58 (2H,t, J=6.1, CH₂ N(CH₃)₂), 3.61 (2H, m, J=11.2 and 6.0,CONHCH,), 7.67 (1H, m, J=7.1, 6.4 and 0.7, H-7), 7.71 (1H,dd, J=8.3 and7.1, H-2), 7.95 (1H, m, J=7.7, 6.7 and 1.4, H-6) 8.18 (1H, dd, J=8.2 and1.3, H-8), 8.18 (1H,dd, J=8.9 and 0.8, H-5), 8.31 (1H,dd, J=8.4 and 1.5,H-1), 8.74 (1H,dd, J=7.1 and 1.6, H-3), 9.23 (1H, s, H-9), 11.73(1H,br.t, J=4.7, CONH).

EXAMPLE 6 Preparation of -[2-(Dimethylamino)ethy]acridine-4-carboxamide,dihydrochloride, trihydrate ##STR19##

To the product of Example 5 (2.93 g, 100 mmol), dissolved in a mixtureof toluene (20.7 ml) and EtOH (9 ml), was added dropwise concentratedHCl (2.0 ml, ca 200 mmol). Precipitation of the salt occurred which wascompleted by the addition of EtOAc (8.6 ml). The mixture was cooled to5° C., stirred for a further 1 hour and the yellowish crystalline saltwas filtered, washed with EtOAc(3×20 ml) and pulled dry on the filter togive the title compound 3.9 g (theory for 2HCl. 3H₂ O, 4.2 g) Hplcindicated it was ca 98% a/a.

The salt was recrystallised by dissolving it in a mixture of EtOH (20ml) and water (2 ml) at 70° C. The resultant solution was diluted withEtOAc (20 ml) maintaining the temperature of the mixture at ca 60-70° C.The mixture was then allowed to cool slowly to produce thedihydrochloride trihydrate as a yellowish crystalline solid which aftercooling in an ice bath for 1 hour was filtered, washed with a chilled10:10:1 mixture of EtOH:EtOAc:water (2×10 ml) and pulled dry on thefilter. It was then allowed to equilibrate in a fume cupboard toconstant weight to give the pure salt (3.6, 85.7%). Hplc, 99.2% a/a. ¹HNMR (DMSO)δ2.90 (6H, s, N(CH₃)₂), 3.46 (2H, m, CH₂ N(CH₃)₂), 3.98 (2H,m, CONHCH₂), 7.75 and 7.80 (2H, t and br.t, H-7 (7.75) and H-2 (7.80)),8.02 (1H, m, H-6), 8.28 (1H,d, H-8), 8.46 (1H,d, H-1), 8.51 (1H, d,H-5), 8.77 (1H,d,H-3), 9.43 (1H,s, H-9), 10.65 (1H, br.s, NH⁺ (CH₃)₂),11.45 (1H, br.t. CONH).

EXAMPLE 7 Preoaration of [2-(dimethylamino)ethy]acridine-4-carboxamide##STR20##

A stirred solution of the aldehyde produced in Example 3 (3.0 g; 11.76mmole) in CH₂ Cl₂ was saturated with nitrogen and boron trifluorideetherate (3.33 g; 23.5 mmole; 2 equivalents) was added dropwise underN₂. The solution became orange (a solid deposited which dissolved after2-3 min), then clear dark red followed by a deposition of a yellowsolid. It was left to stir for 4 hours until the reaction was completeby Tlc (SiO₂ ; CH₃ OH:CH₂ Cl₂ /1:40). A solution of 1M Na₂ CO₃ (15 ml)was added (pH 7) and the solution stirred for 5 min. The lower organiclayer was separated, then washed with 1M Na₂ CO₃ (15 ml). The combinedaqueous layer was extracted with CH₂ Cl₂ (10 ml), the organic layer wasseparated then added to the main organic layer. The combined organiclayer was washed with brine (10 ml), reduced to ca 1/2 volume, thenreevaporated from CH₂ Cl₂ (20 ml). N,N-dimethylethylenediamine (NNDMEDA)was added (5.1 ml, 47.04 mmole, 4 equivalents) and the reaction mixtureconcentrated to remove any remaining CH₂ Cl₂.

The residue was heated in an oil bath (110-120° C.) overnight Tlc (SiO₂; 10% CH₃ OH:CH₂ Cl₂) to give an orange/brown oil which was diluted withtoluene (20 ml) then concentrated to low volume to remove excessNNDMEDA. The residue was diluted with EtOAc (25 ml) then washed with 1MNaHCO₃ solution (15 ml). The organic layer was separated, washed withwater (2×10 ml) then separated. The combined organic layer was stirredwith activated C (300 mg), Kieselguhr (300 mg) for 30 min, filteredthrough a dry Kieselguhr bed, washed with EtOAc and the filtrateconcentrated to a gum (3.2 g) which rapidly crystallised. Upontrituration with EtOAc (2 ml) and hexane (20 ml) a yellowish-brown solidwas obtained. The solid was filtered, washed with hexane then dried invacuo (40° C.) to give the title compound (2.65 g; 77%) as a buff solid.¹ HNMR data were obtained as reported for the product of Example 5.

EXAMPLE 8 Preparation of Compounds of Formula (I) from Compounds ofFormula (VI). ##STR21##

The series of reactions depicted in scheme 2 was carried out to produceDACA, compound 3a, and a series of analogues 3b to 3g. For each of thesecompounds the substituents R¹ and R² throughout scheme 2 had thefollowing definitions

    ______________________________________                                        R.sup.1       R.sup.2 Compounds                                               ______________________________________                                        H             H       a                                                         H 5-CF.sub.3 b                                                                H 6-Me c                                                                      H 6-Er d                                                                      H 6-CF.sub.3 e                                                                6-Me 7-Me f                                                                   7-Me 5-Cl g                                                                 ______________________________________                                    

A solution of methyl 2-[N-(2-carboxyphenyl)amino]benzoate 4a,(10 g, 36.9mmol) in dry THF (200 ml) was treated with 1,1-carbonyldiimidazole (8.97g, 55.4 mmol). The reaction mixture was allowed to stir at roomtemperature for 15 hours, then the THF solution was added slowly to asuspension of NaBH₄ (7.00 g) in H₂ O (200 ml) without isolation of theintermediate imidazolide 5a. The reaction was virtually instantaneousand at the end of the addition the mixture was quenched withconcentrated HCl, partitioned between CH₂ Cl₂ (200 ml) and NaHCO, (200ml), and the organic layer was dried with Na₂ SO₄. Removal of thesolvent and filtration of the residue through a plug of flash-gradesilica gel in petroleum ether/EtOAc (4:1) gave methyl2-[N-(2-hydroxymethyl)phenylamino]benzoate 6a (7.85 g, 83%). Mp (CH₂Cl/petroleum ether) 69-71° C. ¹ H NMR (CDCl)δ1.93 (br.s, 1H, OH), 3.91(s, 3H, COOH CH₃), 4.72 (S, 2H, CH,OH), 6.74 (ddd, J=8.0, 7.0, 1.1 Hz,1H, H-5), 7.08-7.44 (m, 6H, H-3,3', 4,4'5', 6'), 7.97 (dd, J=8.1, 1.6Hz, 1H, H-6) 9.59 (br.s, 1H, NH).

A stirred solution of 6a (7.74 g, 30 mmol) in Me₂ CO (200 ml) wastreated with a suspension of MnO₂ (10 g) for 3 days at room temperature.The MnO₂ was filtered off (Celite) and the Me₂ CO was removed underreduced pressure to yield methyl 2-[N-(2-formyl)phenylamino]benzoate 7a(7.70 g, 100%). A sample crystallised from EtOAc/petroleum ther had mp110-112° C. ¹ H NMR (CDCl²)δ3.95 (s, 3H, OOCH₃), 6.95-7.03 (m, 2H,H-4',5), 7.41-7.45 (m, 2H, H-5',6), 7.50 (br d, J=8.5 Hz, 1H, H-3 orH-6'), 7.61 (br d, J=8.2 Hz, 1H, H-6' or H-3), 7.65 (dd, J=7.7, 1.7 Hz,1H, H-3'), 8.01 (dd, J=7.9. 1.7 Hz, 1H, H-6), 10.00 (s, 1H, CHO), 11.26(br s, 1H, NH).

The aldehyde 7a (210 mg, 0.82 mmol) was placed in a flask which wasflushed with N₂, then trifluoroacetic acid (10 mL) was added and theresultant solution was stirred for 24 hours at room temperature. Solventwas removed under reduced pressure to give crude methylacridine-4-carboxylate 8a (183 mg. 94%). This was diluted with CH₂ Cl₂(100 mL), and neutralised with Et₃ N. Solvents were removed underreduced pressure, and the residue was filtered through a short column offlash silica gel in EtOAc/petroleum ether (1:3) to give methylacridine-4-carboxylate (8a) as an orange oil (1.83 g, 980%) ¹ H NMR(CDCl₃)δ4.12 (s, 3H, COOCH₃), 7.53-7.58 (m,2H,H-2 and H-6 or H-7), 7.79(ddd, J=8.8, 6.6, 1.4 Hz, 1H, H-7 or H-6), 8.00 (dd, J=8.0, 1.0 Hz, 1H,H-1), 8.12-8.14 (m, 2H, H-5, 8), 8.30 (dd, J=8.7,0.9 Hz, 1H, H-3), 8.80(s, 1H, H-9).

A solution of 8a (1.83 g, 7.72 mmol) and N,N-dimethylethylenediamine(3.40 g, 38.6 mmol) in propan-1-ol (80 ml) was flushed with N₂, and themixture was heated at reflux for three days under N₂. Solvent was thenremoved under reduced pressure, and the residue was partitioned betweenCH₂ Cl₂ (100 ml) and 1M Na₂ CO₃ (100 ml). The organic layer wasevaporated and the residue chromatographed on alumina, eluting with CH₂Cl₂ /MeOH (199:1) to giveN-[2-dimethylamino)ethyl]acridine-4-carboxamide 3a (1.38 g, 61%), mp(diHCl salt) 191-195° C., identical with an authentic sample.

An analogous procedure was employed to produce compounds 3b to 3g fromthe starting compounds 4b to 4g, respectively. All the compounds 3b to3g had satisfactory spectroscopic and analytical properties. The yieldof the intermediate aldehydes 7a to 7g from the starting compounds 4a to4g (steps (i) and (ii)) were as follows:

    ______________________________________                                        4              yield (4-7)                                                                             7                                                    ______________________________________                                        4a             83%       7a                                                     4b 100% 7b                                                                    4c 82% 7c                                                                     4d 67% 7d                                                                     4e 77% 7e                                                                     4f 60% 7f                                                                     4g 44% 7g                                                                   ______________________________________                                    

EXAMPLE 9 Preparation of Acridine-4-carboxylic acid

To methyl acridine-4-carboxylate, prepared in Example 4,(183 mg), wasadded a degassed solution of NaOH in aqueous EtOH (1:1,2M)(35 ml). Themixture was stirred for 3 hours at 50° C., when a clear solution wasobtained, then neutralised with glacial AcOH. Extraction with EtOAc(3×15 50 ml) followed by chromatography on silica gel, eluting withEtOAc/petroleum ether (1:4), gave acridine-4-carboxylic acid (160 mg,87%), mp (Me₂ CO) 196-197° C. (lit, mp 202-204° C.).

By the same procedure, other compounds of formula (III) were hydrolysedto the corresponding acridine-4-carboxylic acids.

EXAMPLE 10 Preparation of Compounds of Formula (I) fromAcridine-4-carboxylic Acid Precursor

General method

A suspension of 7-ethylacridine-4-carboxylic acid, produced by theprocedure of Example 9 from a compound of formula (III) wherein R¹ is Hand R² is a 7-ethyl substituent (472 mg, 1.99 mmol), in dry DMF (10 ml)was stirred with 1-11'-carbonyldiimidazole (650 mg, 3.98 mmol) at 20° C.until homogeneous (ca. 12 h). The solution was then cooled to 0° C. andtreated with N,N-dimethylethylenediamine (0.73 g, 9.96 mmol) for 5 min.Solvent was then removed under reduced pressure, and the residue waspartitioned between CH₂ Cl₂ (50 ml) and 1 M aqueous K₂ CO₃ (30 ml). Theorganic layer was washed with water and evaporated, and the residue waschromatographed on alumina. Elution with CH₂ Cl₂ /MeOH (19:1) gaveN-[2-(dimethylamino)ethyl]-7-ethylacridine-4-carboxamide (10a) as ayellow oil (288 mg, 48%). ¹ H NMR (CDCl₃)δ1.35 (t, J=7.6 Hz, 3H CH₂CH₃), 2.36 (s, 6H,N(CH₃)₂), 2.61 (t, J=6.1 Hz, 2H, CH₂ N(CH₃)₂), 2.89(q, J=7.6 Hz, 2H, CH₂ CH₃), 3.63 (q, J=5.6 Hz, 2H, CH₂), 7.73 (dd,J=8.2, 7.2 Hz, 1H, H-2), 7.90 (dd, J=9.0, 1.9 Hz, 1H, H-6), 7.99 (br s,1H, H-8), 8.18 (d, J=8.9 Hz, 1H, H-5), 8.34 (dd, J=8.5, 1.4 Hz, 1H,H-1), 8.73 (dd, J=7.1, 1.5 Hz, 1H, H-3), 9.21 (s, 1H, H-9), 11.81 (br t,J=4.7 Hz, 1H, CONH). Dihydrochloride salt, mp (EtOAc/MeOH) 173-175° C.

The general method above was used to produce the following compounds offormula (I):

N-[2-(Dimethylamino)ethyl-5-ethylacridine-4-carboxamide (compound 10b)(70%), mp (CH₂ Cl₂ /petroleum ether) 106-108° C.; dihydrochloride salt,mp (EtOAc/MeOH) 214-217° C.

N-[2-(Dimethylamino)ethyl]-5-isopropylacridine-4-carboxamide (compound10c) as a yellow oil (76%), dihydrochloride salt, mp (EtOAc/MeOH)213-215° C.

N-[2-(Dimethylamino)ethyl]-5-fluoroacridine-4-carboxamide (compound 1d)(73%), mp (hexane) 95-98.5° C.

N-[2-Dimethylamino)ethyl]-5-bromoacridine-4-carboxamide (compound 10e)(52%), mp 149-150° C.,

N-2-(Dimethylamino)ethyl]-5-trifluoromethylacridine-4-carboxamide(compound 10f) (74%). Hydrochloride salt, mp 207-211° C. (EtOAc/MeOH).

N-[2-(Dimethylamino)ethyl]-6-fluoroacridine-4-carboxamide (compound 10g)(87%), mp (dihydrochloride salt from MeOH/EtOAc) 203-204° C. (dec).

N-[2-(Dimethylamino)ethyl]-6-bromoacridine-4-carboxamide (compound 10h)(676), mp (dihydrochloride salt from MeOH/EtOAc) 161-163° C.

N-[2-(Dimethylamino)ethyl]-7-isopropylacridine-4-carboxamide (compound10i), as a yellow oil (97%), dihydrochloride salt, mp (MeOH/EtOAc)182-187° C.

N-[2-(Dimethylamino)ethyl]-7-t-butylacridine-4-carboxamide (compound10j) (92%), mp (CH₂ Cl₂ /petroleum ether) 128-129° C.

N-[2-(Dimethylamino)ethyl]-7-phenylacridine-4-carboxamide (compound 10k)(64%), mp (CH₂ Cl₂ /petroleum ether) 115-116.5° C., hydrochloride salt,mp (MeOH/EtOAc) 83-85° C.

N-[2-Dimethylamino)ethyl]-7-fluoroacridine-4-carboxamide (compound 101)(74%), mp (MeOH/EtOAc) 128.5-130° C.

N-[2-(Dimethylamino)ethyl]-7-bromoacridine-4-carboxamide (compound 10m),(84%), mp (dihydrochloride salt from MeOH.EtOAc) 181.5-183° C.

EXAMPLE 11 Preparation of Compounds of Formula (I) from MethylAcridine-4-carboxylate Precursor

General Method

A solution of the aldehyde methyl 2-[N-(2-formylphenyl)amino]benzoate (2g, 7.84 mmol) in trifluoroacetic acid (TFA)(20 ml) was degassed andplaced in a two-necked flask which was then flushed with N₂. Thesolution was stirred for 15 hours at room temperature under N₂, and theTFA was then removed under reduced pressure. The resulting oil wasdiluted with CH₂ Cl₂ (100 ml), and the solution was neutralised with Et₃N. Solvents were removed under reduced pressure, and the residue wasfiltered through a short column of flash silica gel in EtOAc/petroleumether (1:3) to give methyl acridine-4-carboxylate as an orange oil (1.83g, 98%). ¹ H NMR (CDCl₃)δ4.12 (s, 3H, CO₂ CH₃), 7.53-7.58 (m, 2H, H-2and H-6 or H-7), 7.79 (ddd, J=8.8, 6.6, 1.4 Hz, 1H, H-7 or H-6), 8.00(dd, J=8.0, 0.8 Hz, 1H, H-1), 8.12-8.14 (m,2H, H-5,8), 8.30 (dd, J=8.7,0.8 Hz, 1H, H-3), 8.80 (s, 1H, H-9).

A solution of methyl acridine 4-carboxylate (1.83 g, 7.72 mmol) andN,N-dimethylethylenediamine (3.40 g, 38.6 mmol) in n-propanol (80 ml)was flushed with N₂, and the mixture was heated at reflux for three daysunder N₂. Solvent was then removed under reduced pressure, and theresidue was partitioned between CH₂ Cl₂ (100 ml) and 1M Na₂ CO₃ (100ml). The organic layer was evaporated and the residue chromatographed onalumina, eluting with CH₂ Cl₂ /MeOH (199:1) to giveN-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) (1.47 g, 61%),mp (dihydrochloride salt from MeOH/EtOAc) 162-165° C.

The general method above was used to produce the following compound offormula (I):

N-[2-(Dimethylamino)ethyl]-6-trifluoromethylacridine-4-carboxamide(compound 11a) (92%), mp. (MeOH/EtOAc) 188-189.5° C.

EXAMPLE 12 Pharmaceutical Composition

Tablets, each weight 0.15 g and containing 25 mg of one of the compoundsof formula (I) can be manufactured as follows:

Composition for 10,000 Tablets

Compound of formula (I) (250 g)

lactose (800 g)

corn starch (415 g)

talc powder (30 g)

magnesium stearate (5 g)

The compound of formula (I), lactose and half the corn starch are mixed.The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch(10 g) is suspended in warm water (90 ml). The resulting paste isgranulated to a powder. The granulate is dried and comminuted on a sieveof 1.4 mm mesh size. The remaining quantity of starch, talc andmagnesium stearate is added, carefully mixed and processed into tablets.

We claim:
 1. A process for producing an acridine carboxamide of formula(I): ##STR22## wherein each of R¹, R², R⁵ and R⁶, which may be the sameor different, is H, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, aryloxy, aralkyloxy,halogen, phenyl, CF₃, NO₂, NH₂, N(R)₂, NHCOR, NHCOOR, NHR⁴, OH, SH, SRor SR₂, wherein R⁴ is H, COR, SO₂ R, COPh, SO₂ Ph or C₁ -C₆ alkyl whichis unsubstituted or substituted by OH or amino, and R is C₁ -C₆ alkyl;or R¹ and R², or R⁵ and R⁶, together form a methylenedioxy group; x isan integer of 1 to 6 and Y is N(R)₂ as defined above; or apharmaceutically acceptable salt thereof, which process comprises:(a)cyclizing a compound of formula (II): ##STR23## wherein R¹, R², R⁵ andR⁶ are as defined above and R3 is C₁ -C₆ alkyl, aryl or aryl-C₁ -C₃alkyl, by treatment with boron trifluoride or a complex thereof toobtain a tetrafluoroborate salt of formula (IIIa): ##STR24## wherein R¹,R², R³, R⁵ and R⁶ are as defined above, followed by treatment of thesalt with an inorganic base in EtOAc or CH₂ Cl₂ to generate a compoundof formula (III); ##STR25## wherein R¹, R², R³, R⁵ and R⁶ are as definedabove; and (b) treating either(i) the compound of formula (III) asdefined above with a primary alkylamine of formula (IV):

    NH.sub.2 (CH.sub.2).sub.2 Y                                (IV)

wherein x and Y are as defined above; or(ii) the carboxylic acidobtainable by hydrolyzing the compound of formula (III) as definedabove, under basic conditions, with a primary alkyl amine of formula(IV) as defined above in the presence of a suitable coupling agent, toobtain a compound of formula (I) as defined above, and (c) if desired,converting one compound of formula (I) into another compound of formula(I), and/or converting a compound of formula (I) into a pharmaceuticallyacceptable salt thereof.
 2. A process for producingN-[2-(dimethylamino)ethy]acridine-4-carboxamide (DACA) of the followingformula: ##STR26## which process comprises (i) treating a compound offormula (VI): ##STR27## wherein R¹, R², R⁵ and R⁶ are H and R³ is C₁ -C₆alkyl, aryl-C₁ -C₃ alkyl or aryl with 1,1'-carbonyldiimidazole in anorganic solvent to obtain a compound of formula (VII): ##STR28## whereinR¹, R², R⁵ and R⁶ are H and R³ 3 is as defined above;(ii) treating thecompound of formula (VII) as defined above with sodium borohydride inthe presence of water to obtain a compound of formula (V): ##STR29##wherein R¹, R², R⁵ and R⁶ are H and R³ is as defined above; (iii)oxidizing the compound of formula (V) as defined above to obtain acompound of formula (II): ##STR30## wherein R¹, R², R⁵ and R⁶ are H andR³ is as defined above; (iv) cyclizing the compound of formula (II) asdefined above by treatment with boron trifluoride or a complex thereofto obtain a tetrafluoroborate salt of formula (IIIa): ##STR31## whereinR¹, R², R³, R⁵ and R⁶ are H and R³ are as defined above, followed bytreatment of the salt with an inorganic base in EtOAc or CH2C12 togenerate a compound of formula (III): ##STR32## wherein R¹, R², R⁵ andR⁶ are H and R³ is as defined above; and (v) treating the compound offormula (III) as defined above with a primary alkylamine of formula(IV):

    NH.sub.2 (CH.sub.2).sub.x Y                                (IV)

wherein x is 2 and Y is N(CH₃)₂, to obtain DACA.
 3. A process accordingto claim 1 wherein R¹, R², R⁵ and R⁶ in formula (II) are H, and informula (IV) x is 2 and Y is N(CH₃)₂, such that the acridine carboxamideof formula (I) produced isN-[2-(dimethylamino)ethy]acridine-4-carboxamide.
 4. A process accordingto claim 1 which further comprises producing the compound of formula(II) by oxidising the corresponding alcohol of formula (V): ##STR33##wherein R¹, R², R³, R⁵ and R⁶ are as defined in claim
 1. 5. A processaccording to claim 4 which comprises producing the alcohol of formula(V) by(a) treating a compound of formula (VI): ##STR34## wherein R¹, R²,R₃, R⁵ and R⁶ are as defined in claim 1, with 1,1'-carbonyldiimidazolein a polar solvent, to obtain a compound of formula (VII): ##STR35##wherein R¹, R², R³, R⁵ and R⁶ are as defined in claim 1, and (b)reducing the compound of formula (VII) as defined above.
 6. A processaccording to claim 5 which further comprises producing the compound offormula (VI) by heating together a mixture of an anthranilic acid offormula (VIII): ##STR36## wherein R¹ and R² are as defined in claim 1,and a 2-iodobenzoic acid ester of formula (IX): ##STR37## wherein R³, R₅and R⁶ are as defined in claim 1, in the presence of a copper catalystand a base in a polar solvent.
 7. A process according to claim 2 whichfurther comprises producing the compound of formula (VI) by heatingtogether anthranilic acid of formula (VIII): ##STR38## wherein R¹ and R²are as defined in claim 2, and a 2-iodobenzoic acid ester of formula(IX): ##STR39## wherein R³, R⁵ and R⁶ are as defined in claim 2, in thepresence of a copper catalyst and a base in a polar solvent.
 8. Aprocess according to claim 2 or 7 which further comprises convertingDACA into a pharmaceutically acceptable salt thereof.
 9. A processaccording to claim 1 or claim 2 which further comprises formulating thecompound of formula (I) or DACA, or a pharmaceutically acceptable saltof a compound of formula (I) or DACA, with a pharmaceutically acceptablecarrier or diluent.
 10. A process according to claim 1 or claim 2wherein the complex of boron trifluoride is the acetic acid complex. 11.A process according to claim 1 or claim 2 wherein the boron trifluorideis used in the form of its etherate BF3O(Et)2.